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Cellular metabolism is crucial for various physiological processes, with folate-dependent one-carbon (1C) metabolism playing a pivotal role. Folate, a B vitamin, is a key cofactor in this pathway, supporting DNA synthesis, methylation processes, and antioxidant defenses. In dividing cells, folate facilitates nucleotide biosynthesis, ensuring genomic stability and preventing carcinogenesis. Additionally, in neurodevelopment, folate is essential for neural tube closure and central nervous system formation. Thus, dysregulation of folate metabolism can contribute to pathologies such as cancer, severe birth defects, and neurodegenerative diseases. Epidemiological evidence highlights folate's impact on disease risk and its potential as a therapeutic target. In cancer, antifolate drugs that inhibit key enzymes of folate-dependent 1C metabolism and strategies targeting folate receptors are current therapeutic options. However, folate's impact on cancer risk is complex, varying among cancer types and dietary contexts. In neurodegenerative conditions, including Alzheimer's and Parkinson's diseases, folate deficiency exacerbates cognitive decline through elevated homocysteine levels, contributing to neuronal damage. Clinical trials of folic acid supplementation show mixed outcomes, underscoring the complexities of its neuroprotective effects. This review integrates current knowledge on folate metabolism in cancer and neurodegeneration, exploring molecular mechanisms, clinical implications, and therapeutic strategies, which can provide crucial information for advancing treatments.

A number of essential nutrients are involved in the folate cycle, and its effectiveness depends on the sufficient intake of them. In addition, polymorphic variants of the methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR) and methionine synthase (MTR) genes affect a wide range of biochemical reactions of the folate cycle and should also be considered as a risk factor for the development of a number of diseases. The purpose of this research was to study the prevalence of these risk factors. Material and methods . The prevalence of polymorphisms of the folate cycle genes: C677T polymorphism of the MTHFR gene and A66G polymorphism of the MTRR gene in a random stratified (by sex and age) sample of the adult population of the Omsk region [n=139, 51 men, 88 women, aged 18 to 75 years, median age 37 (26; 48) years] was studied. The identification of polymorphisms was carried out by the method of allele-specific polymerase chain reaction with an electrophoretic detection scheme. Using the food intake frequency questionnaire, the dietary intake of nutrients involved in the folate cycle was determined: B vitamins (B6, B2, B9, B12), methionine, choline, in a representative stratified sample of residents of the Omsk region [n=421, 177 men, 244 women, aged 18 to 83 years, median age 37 (23; 57) years]. Results . MTHFR genotypes (A222V С677T C>T) were distributed as follows: CC-type - 51.3%, CT - 41.0%, TT - 7.7%; MTRR genotypes (I22M A>G): AA type - 57.9%, AG - 30.3%, GG - 11.8%. The analysis of actual nutrition showed consumption below the recommended dietary intake of folates in 88.2% persons, vitamin B2 and choline - in 40.5%, vitamin B6 - in 29.2%, methionine - in 22.0%. Vitamin B12 intake was within the recommended range. Conclusion . The totality of the data presented indicates the combined influence and wide distribution of factors that determine the low efficiency of the folate cycle, and, as a result, a high risk of developing a characteristic pathology for the adult population of the region, which determines the need and priorities for prevention measures, including healthy nutrition., Competing Interests: The authors declare no conflict of interest., (Copyright© GEOTAR-Media Publishing Group.)

Background: Summary data indicate that it has increased attention to the study of the role of the folate cycle and the genes encoding its key components in the complicated course of the neonatal period in premature infants. Therefore, the aim of our study was to investigate the relationship of folate cycle gene variants with the features of the neonatal course in premature infants with severe intraventricular hemorrhages (IVH)., Methods: The study included 24 preterm infants with with IVHs of 3d and 4th degree that received standard clinical, laboratory and instrumental examination., Results: Apgar scores at 1 and 5 minutes were significantly lower in patients with AA genotype according to variant A1298C of the MTHFR gene. The concentration of total protein on 6th day after birth was negatively correlated with the A66G variant of the MTRR gene. The mean concentration of ionized calcium in the first day after birth was higher in the subgroup of patients with the AA genotype (according to variant A1298C of the MTHFR gene). In the subgroup of patients requiring mechanical ventilation, the frequency of AA genotype according to variant A2756G of the MTR gene was significantly increased. The presence of respiratory disorders and oxygen dependence was negatively correlated with variant A1298C MTHFR. The day of surfactant administration was positively correlated with variant A1298C of the MTHFR gene., Conclusion: The results of this study indicate that gene variants MTHFR (C677T, A1298C), MTRR (A66G), MTR (A2756G), RFC1 (G80A) may affect the neonatal course in premature infants with severe IVH.

Folate metabolism supplies one-carbon (1C) units for biosynthesis and methylation and has long been a target for cancer chemotherapy. Mitochondrial serine catabolism is considered the sole contributor of folate-mediated 1C units in proliferating cancer cells. Here, we show that under physiological folate levels in the cell environment, cytosolic serine-hydroxymethyltransferase (SHMT1) is the predominant source of 1C units in a variety of cancers, while mitochondrial 1C flux is overly repressed. Tumor-specific reliance on cytosolic 1C flux is associated with poor capacity to retain intracellular folates, which is determined by the expression of SLC19A1, which encodes the reduced folate carrier (RFC). We show that silencing SHMT1 in cells with low RFC expression impairs pyrimidine biosynthesis and tumor growth in vivo. Overall, our findings reveal major diversity in cancer cell utilization of the cytosolic versus mitochondrial folate cycle across tumors and SLC19A1 expression as a marker for increased reliance on SHMT1., Competing Interests: Declaration of Interests W.D.L. and T.S. declare that the results presented in this work were included in a submitted Provisional Patent application (#62/901,920). The other authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The oleaginous fungus Mortierella alpina can synthesize a variety of polyunsaturated fatty acids, which are used extensively in industry for the production of arachidonic acid (AA). NADPH is the limiting factor and critical reducing agent in lipid biosynthesis. In the folate cycle, methylenetetrahydrofolate dehydrogenase (MTHFDL) catalyzes the conversion of methylene tetrahydrofolate into 10-formyl-tetrahydrofolate with the reduction of NADP + to NADPH. MTHFDL RNAi was used to investigate the role of the folate cycle in lipogenesis. Gene knockdown decreased the transcript levels of MTHFDL by about 50 % and attenuated cell fatty acid synthesis. The observation of decreased NADPH levels and downregulated NADPH-producing genes in response to MTHFDL RNAi indicates a novel aspect of the NADPH regulatory mechanism. Thus, our study demonstrates that MTHFDL plays key role in the mediation of NADPH in lipogenesis in M. alpina .

By means of visiting folic acid processing plant, this article introduces the structure, metabolism and mechanism of folic acid, and the recommendations for folic acid supplementation are given. In order to help those who need to take folic acid supplements, this article also provides a deep understanding of the functions of folic acid in the body by combining scientific and entertaining ways. [ABSTRACT FROM AUTHOR]

Background: The folate cycle of one-carbon (C1) metabolism, which plays a central role in the biosynthesis of nucleotides and amino acids, demonstrates the significance of metabolic adaptation. We investigated the evolutionary history of the methylenetetrahydrofolate dehydrogenase (mTHF) gene family, one of the main drivers of the folate cycle, across life. Results: Through comparative genomic and phylogenetic analyses, we found that several lineages of Archaea lacked domains vital for folate cycle function such as the mTHF catalytic and NAD(P)-binding domains of FolD. Within eukaryotes, the mTHF gene family diversified rapidly. For example, several duplications have been observed in lineages including the Amoebozoa, Opisthokonta, and Viridiplantae. In a common ancestor of Opisthokonta, FolD and FTHFS underwent fusion giving rise to the gene MTHFD1, possessing the domains of both genes. Conclusions: Our evolutionary reconstruction of the mTHF gene family associated with a primary metabolic pathway reveals dynamic evolution, including gene birth-and-death, gene fusion, and potential horizontal gene transfer events and/or amino acid convergence. [ABSTRACT FROM AUTHOR]

Folate, also known as vitamin B9, plays a crucial role in the one-carbon (1C) metabolism, a conserved pathway from microbes to humans. The 1C metabolism, consisting of the folate and methionine cycles, is essential in many biological processes such as nucleotide and protein biosynthesis, cell proliferation, and embryonic development. Despite its functional role, little is known about the 1C metabolism in crustaceans. As part of an ongoing effort to characterize important pathways in Calanus finmarchicus, the biomass-dominant zooplankton in much of the North Atlantic Ocean, we identified transcripts encoding the 1C metabolism enzymes. Using an in silico workflow consisting of a transcriptome mining, reciprocal blasts, and structural analyses of the deduced proteins, we identified the entire set of enzymes in both cycles. The majority encoded for full-length proteins and clustered with homologs from other species. Stage-specific expression was reported, with several transcripts showing high expression in the naupliar stage (e.g., 10-FTHFD, SHMT2) while some methyltransferases (e.g., BHMT, SHMT, DNMT) were more expressed in adults. Overall, this study provides a set of genes which can be used as potential biomarkers of development and reproduction and can be tested in other zooplankters to assess ocean health status monitoring. [ABSTRACT FROM AUTHOR]

Funicular myelosis (subacute combined degeneration) is a disease characterized by the development of degeneration of the posterior and lateral cords of the spinal cord. Funicular myelosis is a neurological complication of vitamin B12 deficiency, which occurs as a result of reduced intake of vitamin B12 with food, malabsorption, in connection with taking some drugs (metformin, proton pump inhibitors, and nitrous oxide), with invasion by Diphyllobothrium latum. The disease is usually characterized by the presence of paresthesias, the development of sensitive ataxia, and impaired gait. The aim of the work was to demonstrate a clinical case of funicular myelosis in a young patient in order to improve the diagnostic process, paying attention to the genetic profile and identifying a concomitant predisposition to folate cycle disorder. A clinical case of funicular myelosis in a 39-year-old woman is described. The patient came to the neurology department with complaints of numbness in the upper and lower limbs, periodic shooting pains along the spine when the head is tilted forward. During the neurological examination, the following was observed: a decrease in vibrational, muscle-joint, discrimination sensitivity in the upper limbs, paresthesias in the distal parts of the limbs, and sensitive ataxia. According to the results of the magnetic resonance imaging (MRI) of the spinal cord, a lesion of the posterior cords on the long segment (C2-Th1) was found, which corresponds to the subacute degeneration of the spinal cord, which arose due to the deficiency of holotranscobalamin (active B12). The patient received appropriate treatment and was discharged home. Subsequently, the patient was found to have a concomitant genetic predisposition to folate cycle disorder and the development of thrombophilia. A year later, the woman again came to the neurological department. We carried out a repeated examination, evaluation of the results of the MRI of the cervical spine and other examinations in dynamics. According to the results of the literature analysis, additional markers for the diagnosis of funicular myelosis (in particular, homocysteine), the causes of hyper-homocysteinemia and its effects on the body were described. Timely detection and treatment of vitamin B12 deficiency is quite important, since in severe cases the development of spastic paraplegia is possible. Recovery of lost functions depends on the extent of spinal cord damage and the duration of the disease. If anemia is observed together with neurological symptoms, it is necessary to be especially attentive to possible funicular myelosis and to carry out appropriate diagnostic searches. And when detecting hyper-homocysteinemia, it is advisable to take into account other factors that can cause an increase in the level of homocysteine, in addition to a deficiency of vitamins B6, B12 and folic acid. [ABSTRACT FROM AUTHOR]

Several maternal genetic variations are known to play an important role during pregnancy since they can affect mother health and/or fetal growth. The frequency of these variants is variable among different populations. This study aimed to investigate thrombophilia, folate metabolism and hypertension genetic variants in reproductive age women of Rostov region (Russia) and then assess their linkage disequilibrium (LD) and heterogeneity among populations. A total of 3108 reproductive age women were included (33.75 ± 5.13 years). Twenty‐one genetic variants were detected with RT‐PCR. LD was tested according to (D′) coefficient and p value. The highest frequency of mutant allele in studied population was as follows: PAI‐1 rs1799768, MTRR rs1801394, AGT rs699, and AGTR2 rs1403543. We showed a high possibility of coinheritance of MTHFR rs1801133 with rs1801131 and AGT rs699 with rs4762 (D′=0.992 and 0.999, respectively). In addition, comparative analysis showed F7 rs6046, FGB rs1800790, MTR rs1805087, and AGT rs699 significantly more frequent among Rostov females by 1.3–1.5 times than European. MTHFR rs1801133, ADD1 rs4961, AGTR2 rs1403543, NOS3 rs2070744, and rs1799983 were with higher frequencies in Europeans than those in the studied group. Our data could be used as a reference for further associative studies of targeted genetic variations in different pregnancy complications specifically in this population. [ABSTRACT FROM AUTHOR]

Introduction. Hyperhomocysteinemia (HHC) is one of the arms in the pathogenesis of thrombotic complications in female cancer patients.Aim: to assess an HHC-related impact to developing thrombotic complications in patients with malignant neoplasms of the female genital organs and breast cancer.Materials and Methods. There were retrospectively evaluated the data collected from 236 patients: with ovarian tumors (n = 63), cervical cancer (n = 51), breast tumors (n = 64), malignant neoplasms of the uterine body (n = 58). The control group consisted of 50 women without malignant neoplasms. The analysis of homocysteine (HC) concentration, the frequency of polymorphisms of the genes encoding folate cycle enzymes MTHFR C677T, MTHFR A1298C, MTRR A66G, MTR A2756G as well as the rate of thrombotic complications was carried out. A risk of blood HC level-related thrombotic complications was assessed.Results. Plasma HC concentration comprised ≥ 22 μmol/l in 30.5 % of patients. Thrombotic complications within one year after discharge from the hospital were developed in 15.3 % cases. The risk of thrombotic complications turned out to be higher in patients with elevated plasma HC level (≥ 22 μmol/l) (odds ratio = 2.99; 95 % confidence interval = 1.11–8.08). No significantly increased prevalence of polymorphisms in the genes encoding folate cycle enzymes among female cancer patients was detected.Conclusion. Monitoring HC level in female cancer patients contributes separately to predict a likelihood of thrombotic complications. Prescribing drugs that reduce HC level (folic acid) and monitoring its concentration in female cancer patients during therapy, including chemotherapy, can potentially lower an incidence of thrombotic complications.

Low serum folate levels are inversely related to metabolic associated fatty liver disease (MAFLD). The role of the folate transporter gene (SLC19A1) was assessed to clarify its involvement in lipid accumulation during the onset of MAFLD in humans and in liver cells by genomic, transcriptomic, and metabolomic techniques. Genotypes of 3 SNPs in a case-control cohort were initially correlated to clinical and serum MAFLD markers. Subsequently, the expression of 84 key genes in response to the loss of SLC19A1 was evaluated with the aid of an RT2 profiler-array. After shRNA-silencing of SLC19A1 in THLE2 cells, folate and lipid levels were measured by ELISA and staining techniques, respectively. In addition, up to 482 amino acids and lipid metabolites were semi-quantified in SLC19A1-knockdown (KD) cells through ultra-high-performance liquid chromatography coupled with mass spectrometry. SNPs, rs1051266 and rs3788200, were significantly associated with the development of fatty liver for the single-marker allelic test. The minor alleles of these SNPs were associated with a 0.6/−1.67-fold decreased risk of developing MAFLD. When SLC19A1 was KD in THLE2 cells, intracellular folate content was four times lower than in wild-type cells. The lack of functional SLC19A1 provoked significant changes in the regulation of genes associated with lipid droplet accumulation within the cell and the onset of NAFLD. Metabolomic analyses showed a highly altered profile, where most of the species that accumulated in SLC19A1-KD-cells belong to the chemical groups of triacylglycerols, diacylglycerols, polyunsaturated fatty acids, and long chain, highly unsaturated cholesterol esters. In conclusion, the lack of SLC19A1 gene expression in hepatocytes affects the regulation of key genes for normal liver function, reduces intracellular folate levels, and impairs lipid metabolism, which entails lipid droplet accumulation in hepatocytes. [ABSTRACT FROM AUTHOR]

Cancer cells are characterized by accelerated proliferation and an outstanding adaptation of their metabolic pathways to meet energy demands. The folate cycle, also known as folate metabolism or one-carbon metabolism, through enzymatic interconversions, provides metabolites necessary for nucleotide synthesis, methylation, and reduction power, helping to maintain the high rate of proliferation; therefore, the study of this metabolic pathway is of great importance in the study of cancer. Moreover, multiple enzymes involved in this cycle have been implicated in different types of cancer, corroborating the cell's adaptations under this pathology. During the last decade, nonalcoholic fatty liver disease has emerged as the leading etiology related to the rise in the incidence and deaths of hepatocellular carcinoma. Specifically, cholesterol accumulation has been a determinant promoter of tumor formation, with solid evidence that an enriched-cholesterol diet plays a crucial role in accelerating the development of an aggressive subtype of hepatocellular carcinoma compared to other models. In this review, we will discuss the most recent findings to understand the contribution of folate metabolism to cancer cells and tumor microenvironment while creating a link between the dynamics given by cholesterol and methylenetetrahydrofolate dehydrogenase 1-like, a key enzyme of the cycle located in the mitochondrial compartment. [ABSTRACT FROM AUTHOR]

Study background objectives: Cancer poses a significant health concern as it is incurable. Every year, research on how to treat and eradicate this chronic condition is done. This systematic review will unmask the recent developments concerning highly active 1C metabolism with regard to cancer diagnosis, treatment, and drug resistance. The significance of this study is rolling out evidence-based evidence on the importance of one-carbon metabolism in cancer diagnosis and treatment. Methods: Eight randomized controlled trials (RCTs) were reviewed from five electronic databases - EMBASE, Scopus Review, Google Scholar, Web of Science, and PubMed. Outcomes from the eight studies were analyzed to paint a picture of the topic in question. While the Preferred Reporting Items for Systematic Reviews and Meta-Analysis' (PRISMA) protocol guided the initial literature search, The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach informed quality assessments of the eligible studies. Conclusion: Since its emergence in the 1980s, 1C metabolism has been investigated and broadened to capture essential aspects of cancer treatment, diagnosis, and drug resistance. The review found that metabolites like folic acid could be used to detect different types of cancer. The metabolic pathways could induce tumorigenesis and DNA methylation, hence drug resistance. [ABSTRACT FROM AUTHOR]

BACKGROUND: Summary data indicate that it has increased attention to the study of the role of the folate cycle and the genes encoding its key components in the complicated course of the neonatal period in premature infants. Therefore, the aim of our study was to investigate the relationship of folate cycle gene variants with the features of the neonatal course in premature infants with severe intraventricular hemorrhages (IVH). METHODS: The study included 24 preterm infants with with IVHs of 3d and 4th degree that received standard clinical, laboratory and instrumental examination. RESULTS: Apgar scores at 1 and 5 minutes were significantly lower in patients with AA genotype according to variant A1298C of the MTHFR gene. The concentration of total protein on 6th day after birth was negatively correlated with the A66G variant of the MTRR gene. The mean concentration of ionized calcium in the first day after birth was higher in the subgroup of patients with the AA genotype (according to variant A1298C of the MTHFR gene). In the subgroup of patients requiring mechanical ventilation, the frequency of AA genotype according to variant A2756G of the MTR gene was significantly increased. The presence of respiratory disorders and oxygen dependence was negatively correlated with variant A1298C MTHFR. The day of surfactant administration was positively correlated with variant A1298C of the MTHFR gene. CONCLUSION: The results of this study indicate that gene variants MTHFR (C677T, A1298C), MTRR (A66G), MTR (A2756G), RFC1 (G80A) may affect the neonatal course in premature infants with severe IVH. [ABSTRACT FROM AUTHOR]

Cystathionine beta-synthase deficient homocystinuria (HCU) is a life-threatening disorder of sulfur metabolism. Our knowledge of the metabolic changes induced in HCU are based almost exclusively on data derived from plasma. In the present study, we present a comprehensive analysis on the effects of HCU upon the hepatic metabolites and enzyme expression levels of the methionine-folate cycles in a mouse model of HCU. HCU induced a 10-fold increase in hepatic total homocysteine and in contrast to plasma, this metabolite was only lowered by approximately 20% by betaine treatment indicating that this toxic metabolite remains unacceptably elevated. Hepatic methionine, S -adenosylmethionine, S -adenosylhomocysteine, N -acetlymethionine, N -formylmethionine, methionine sulfoxide, S -methylcysteine, serine, N -acetylserine, taurocyamine and N -acetyltaurine levels were also significantly increased by HCU while cysteine, N -acetylcysteine and hypotaurine were all significantly decreased. In terms of polyamine metabolism, HCU significantly decreased spermine and spermidine levels while increasing 5′-methylthioadenosine. Betaine treatment restored normal spermine and spermidine levels but further increased 5′-methylthioadenosine. HCU induced a 2-fold induction in expression of both S -adenosylhomocysteine hydrolase and methylenetetrahydrofolate reductase. Induction of this latter enzyme was accompanied by a 10-fold accumulation of its product, 5-methyl-tetrahydrofolate, with the potential to significantly perturb one‑carbon metabolism. Expression of the cytoplasmic isoform of serine hydroxymethyltransferase was unaffected by HCU but the mitochondrial isoform was repressed indicating differential regulation of one‑carbon metabolism in different sub-cellular compartments. All HCU-induced changes in enzyme expression were completely reversed by either betaine or taurine treatment. Collectively, our data show significant alterations of polyamine, folate and methionine cycle metabolism in HCU hepatic tissues that in some cases, differ significantly from those observed in plasma, and have the potential to contribute to multiple aspects of pathogenesis. [ABSTRACT FROM AUTHOR]

Aim: to show the effect of genetically determined folate cycle deficiency in children with autism spectrum disorders (ASD).Participants: 89 children (57 boys; 32 girls, Ukraine, 2-10 years old); participants were diagnosed with ASD. The control group consisted of 34 children with ASD.Diagnostic methods:polymerase chain reaction (PCR), complex immunological research, diagnosis of infection, determination of biomarkers.Results and discussion:Hyperhomocysteinemia was revealed in 87% of cases (p <0.05; Z

The folate pathway is critical to proper cellular function and metabolism. It is responsible for multiple functions, including energy (ATP) production, methylation reactions for DNA and protein synthesis and the production of immunomodulatory molecules, inosine and adenosine. These play an important role in immune signaling and cytotoxicity. Herein, we hypothesize that defects in the folate pathway in genetically susceptible individuals could lead to immune dysfunction, permissive environments for chronic cyclical latent/lytic viral infection, and, ultimately, the development of unchecked autoimmune responses to infected tissue, in this case islet beta cells. In the context of type 1 diabetes (T1D), there has been a recent increase in newly diagnosed cases of T1D in the past 20 years that has exceeded previous epidemiological predictions with yet unidentified factor(s). This speaks to a potential environmental trigger that adversely affects immune responses. Most research into the immune dysfunction of T1D has focused on downstream adaptive responses of T and B cells neglecting the role of the upstream innate players such as natural killer (NK) cells. Constantly, surveilling the blood and tissues for pathogens, NK cells remove threats through direct cytotoxic responses and recruitment of adaptive responses using cytokines, such as IL-1β and IFN-γ. One long-standing hypothesis suggests viral infection as a potential trigger for the autoimmune response in T1D. Recent data suggest multiple viruses as potential causal agents. Intertwined with this is an observed reduced NK cell enumeration, cytotoxicity, and cytokine signaling in T1D patients. Many of the viruses implicated in T1D are chronic latent/lysogenic infections with demonstrated capacity to reduce NK cell response and number through mechanisms that resemble those of pregnancy tolerance. Defects in the folate pathway in T1D patients could result in decreased immune response to viral infection or viral reactivation. Dampened NK responses to infections result in improper signaling, improper antigen presentation, and amplified CD8+ lymphocyte proliferation and cytotoxicity, a hallmark of beta cell infiltrates in patients with T1D onset. This would suggest a critical role for NK cells in T1D development linked to viral infection and the importance of the folate pathway in maintaining proper NK response.

The folate pathway is critical to proper cellular function and metabolism. It is responsible for multiple functions, including energy (ATP) production, methylation reactions for DNA and protein synthesis and the production of immunomodulatory molecules, inosine and adenosine. These play an important role in immune signaling and cytotoxicity. Herein, we hypothesize that defects in the folate pathway in genetically susceptible individuals could lead to immune dysfunction, permissive environments for chronic cyclical latent/lytic viral infection, and, ultimately, the development of unchecked autoimmune responses to infected tissue, in this case islet beta cells. In the context of type 1 diabetes (T1D), there has been a recent increase in newly diagnosed cases of T1D in the past 20 years that has exceeded previous epidemiological predictions with yet unidentified factor(s). This speaks to a potential environmental trigger that adversely affects immune responses. Most research into the immune dysfunction of T1D has focused on downstream adaptive responses of T and B cells neglecting the role of the upstream innate players such as natural killer (NK) cells. Constantly, surveilling the blood and tissues for pathogens, NK cells remove threats through direct cytotoxic responses and recruitment of adaptive responses using cytokines, such as IL-1β and IFN-γ. One long-standing hypothesis suggests viral infection as a potential trigger for the autoimmune response in T1D. Recent data suggest multiple viruses as potential causal agents. Intertwined with this is an observed reduced NK cell enumeration, cytotoxicity, and cytokine signaling in T1D patients. Many of the viruses implicated in T1D are chronic latent/lysogenic infections with demonstrated capacity to reduce NK cell response and number through mechanisms that resemble those of pregnancy tolerance. Defects in the folate pathway in T1D patients could result in decreased immune response to viral infection or viral reactivation. Dampened NK responses to infections result in improper signaling, improper antigen presentation, and amplified CD8+ lymphocyte proliferation and cytotoxicity, a hallmark of beta cell infiltrates in patients with T1D onset. This would suggest a critical role for NK cells in T1D development linked to viral infection and the importance of the folate pathway in maintaining proper NK response. [ABSTRACT FROM AUTHOR]

Allelic variants of folate cycle enzyme genes can contribute to predisposition to cancer. The impact of polymorphic loci A2756G of MTR gene and of C1420T of SHMT1 gene for the risk of prostatic cancer was studied in residents of West Siberia. The frequency of alleles of these loci in patients ( N = 371) and controls ( N = 285) was determined and the data were statistically processed. No statistically significant association with prostatic cancer was detected for any of the studied loci. [ABSTRACT FROM AUTHOR]

Background: In recent years, the interest in genetic predisposition studies for coronary artery disease and restenosis has increased. Studies show that polymorphisms of genes encoding folate cycle and homocysteine metabolism enzymes significantly contribute to atherogenesis and endothelial dysfunction. The purpose of this study was to examine some SNPs of genes coding for folate cycle enzymes and DNA methyltransferases as risk factors for in-stent restenosis. Methods: The study included 113 patients after stent implantation and 62 patients without signs of coronary artery disease at coronary angiography as the control group. Real-time PCR and RFLP-PCR were applied to genotype all participants for MTHFR rs1801133, MTHFR rs1801131, MTR rs1805087, MTRR rs1801394, DNMT1 rs8101626, DNMT3B rs1569686, and DNMT3B rs2424913 gene polymorphisms. Statistical data processing was carried out using the R language and the SPSS Statistics 20 software. Results: Statistically significant differences in the DNMT3B gene polymorphisms were found between patients with and without in-stent restenosis. An association of TT rs1569686 and TT rs2424913 genotypes with the development of restenosis was revealed. The TT rs1569686 genotype was more frequent in the patients under the age of 65 years and in the subgroup of patients with post-12-month restenosis, as was the minor GG genotype for MTR rs1805087. The homozygous TT genotype for MTHFR rs1801133 was significantly more frequent in the subgroup over 65 years old. The frequencies of the heterozygous genotype for the MTRR gene and the minor GG homozygotes for the DNMT1 gene were significantly higher in the subgroup with in-stent restenosis under 65 years old. Conclusions: The results of this study could be used for a comprehensive risk assessment of ISR development, determining the optimal tactics and an individual approach in the treatment of patients with coronary artery disease before or after percutaneous coronary interventions, including homocysteine-lowering treatment in patients with hyperhomocysteinemia and a high risk of in-stent restenosis. [ABSTRACT FROM AUTHOR]